Hydrogels can be characterized by three-dimensional networks of polymer chains that can reversibly be deformed. They absorb polar solvents such as water and they find applications in for example medical applications including bone transplants and tissue adhesives, drug delivery systems, cosmetics, pharmaceuticals and in water management.
Hydrogels can occur in the cross-linked form or in the uncross-linked form. Cross-linking usually provides higher viscosities due to an apparent or real increase of the molecular weight and often results into the formation of gels.
Cross-linking can be achieved chemically by the formation of covalent bonds or physically by the formation of e.g. hydrogen bonds or ionic interactions. Obviously, cross-linking can also be achieved both chemically and physically.
Chemical cross-linking of hydrophilic polymers is a general and often applied route to obtain hydrogels. In order to be able to administer or process these gels, prepolymers are dissolved in water and are then polymerized resulting in (in situ) hydrogel formation. Hydrogellation procedures are often based on the use of acrylic or methacrylic macromonomers that are not preferred in (biomedical) applications, because of their inherent toxicity and because they usually require an auxiliary, potentially hazardous, initiator for polymerization. Moreover, cross-linked hydrogels lack reversibility and are limited in their degradation behaviour, as poly(acrylates) and poly(methacrylates) are not biodegradable. For example, U.S. Pat. No. 5,410,016 discloses hydrogels based on copolymers of poly(ethylene glycol) with poly(DL-lactide) containing pendant acrylate functions that are cross-linked in situ. WO 01/44307 discloses hydrogels based on polyvinyl alcohol modified with pendant acrylate and methacrylate groups that are chemically cross-linked in situ. Hence, in both patents an irreversible cross-linked hydrogel is obtained by starting from water processable prepolymers that contain reactive groups.
Hydrogels based on natural polymers, especially collagen, are biocompatible and mostly thermally reversible (Mooney et al. Chem. Rev. 101, page 1869, 2001). However, the mechanical properties of these gels are limited and hardly, if at all, tunable. Especially the mechanical strength in these materials is too low, and often an additional chemical modification is required to make them stronger. However, this results in a reduced biocompatibility and a reduced biodegradation.
U.S. Pat. No. 4,942,035 and U.S. Pat. No. 5,548,035 disclose hydrogels based on block-copolymers in which hydrophilic blocks are alternated by hydrophobic blocks. For example, U.S. Pat. No. 4,942,035 discloses a triblock copolymer consisting of a polyethylene glycol middle block surrounded by two poly(D,L-lactide-co-glycolide) polyester blocks (weight ratio of polyester to PEG at least 1) was prepared and showed gelling behaviour in water. The hydrogels are formed because of phase separation of the hard hydrophobic polyester block, and consequently the relative amount of the hydrophobic polymer needs to be high to counterbalance the hydrophilicity of the polyethylene glycol block to guarantee the gelling behaviour. Therefore, the range of mechanical properties of these gels is limited—for examples with respect to the elasticity—as these properties are mainly governed by the hard block.
WO99/07343 discloses thermally reversible hydrogels intended for uses in drug delivery applications that are based on a hydrophilic polyethylene glycol block and hydrophobic PLLA (poly-L-lactic acid) blocks. The gelling is governed by the presence of the crystalline hard blocks formed by the PLLA. The presence of the crystalline PLLA-blocks limits the mechanical properties and the biodegradation of these materials to a great extent.
U.S. Pat. No. 6,818,018 discloses hydrogels that can be formed in a mammal in situ by providing a system comprising a first polymer that is capable to form physical cross-links and a second polymer that is capable to form chemical cross-links. The first polymer may be selected from a wide group of materials including ionomers whereas the second polymer may be selected from virtually any material that has chemical groups capable of forming covalent bonds.
U.S. Pat. No. 5,883,211 discloses a thermo-reversible hydrogel comprising an uncrosslinked copolymer based on poly(acrylamide) containing up to six different monomers with hydrogen bonding N-substituent groups. The relative content of these monomers with hydrogen bonding N-substituent groups in the uncrosslinked copolymer needs to be higher than 50% to display thermo-reversible gelling behaviour.
In general, “supramolecular chemistry” is understood to be the chemistry of physical or non-covalent, oriented, multiple (at least two), co-operative interactions. For instance, a “supramolecular polymer” is an organic compound that has polymeric properties—for example with respect to its rheological behaviour—due to specific and strong secondary interactions between the different molecules. These physical or non-covalent supramolecular interactions contribute substantially to the properties of the resulting material.
Supramolecular polymers comprising of (macro)molecules that bear hydrogen bonding units can have polymer properties in bulk and in solution, because of the hydrogen bridges between the molecules. Sijbesma et al. (see U.S. Pat. No. 6,320,018 and Science, 278, 1601) have shown that in cases where a self-complementary quadruple hydrogen bonding unit (4H-unit) is used, the physical interactions between the molecules become so strong that polymers with much improved material properties can be prepared.
Several telechelic polymers have been modified with 4H-units, as has been disclosed by Folmer, B. J. B. et al., Adv. Mater. 2000, Vol. 12, 874, in Hirschberg et al., Macromolecules 1999, Vol. 32, 2696, and in WO 02/46260. However, the behaviour and properties of the disclosed polymers in aqueous solution were not studied, and most presumably they do not dissolve in water or have little affinity with water due to their apolar backbones (for example, poly(ethylene butylene)s, polysiloxanes and polybutylene oxides have been prepared). Moreover, these polymers contain the 4H-unit only at the (two) termini of the polymer chain, limiting the mechanical properties of the resulting materials.
A poly(ethylene-propylene)oxide co-polymer (PEO-PPO-polymer) having three alcohol end groups was modified with 4H-units (cf. Lange et al. J. Polym. Sci. A, 1999, 3657 and WO02/098377). The modified polymer was soluble in organic solvents such as chloroform and THF and it appeared that the viscosity of the polymer was significantly effected by the polarity of the solvent. For example, addition of water to a solution of the polymer resulted in a significant decrease of the viscosity due to breaking of the hydrogen bonds between polymer molecules and formation of hydrogen bonds between polymer molecules and water molecules. However, the viscosity was still much higher than that of a solution comprising as reference a low molecular weight compound bearing one 4H-unit. Anyway, due to the relatively high PPO-content (63%) of the PEO-PPO copolymer, this material will hardly, if at all, dissolve in water and the polymers are also not tested in water.
U.S. Pat. No. 6,803,447, incorporated by reference herein for the US patent practice, discloses chemistry to acquire polymers with grafted quadruple H-bonding units. For example, polyacrylates and polymethacrylates with grafted 4H-units have been produced using different kinds of polymerization techniques. However, these polymers do not contain biodegradable components, and have not been tested in water.
WO 03/032929 discloses inter alia a non-biodegradable polysiloxane of which the backbone is functionalized with 4H-units. WO 03/032929 discloses also a polyethyleneoxide polymer comprising two 4H-units and a polyvinyl alcohol comprising about 5 to about 25 4H-units. These two latter polymers are for examples formulated in a styling gel comprising 0.4 wt % of a high molecular weight gelling agent (Carbopol 980), 3.8 wt. % of the polymer, and 84.6 wt. % water to which additionally 10 wt % ethanol as cosolvent is added (cf. Example 5) apparently in order to make these polymers processable.
EP A 1392222 discloses inter alia a telechelic poly(ethylene-propylene)oxide co-polymer (PEO-PPO-polymer) having three alcohol end groups that is modified with 4H-units resulting in a non-water processable polymer. Nevertheless, in example C of this patent a hairstyling gel is described with only 0.2 wt % of the PEO-PPO-polymer containing 4H-units, in an aqueous composition that further contains 1.0 wt % of a gelling agent based on cross-linked high molecular weight polyacrylate and 17 wt % ethanol as cosolvent. Apparently, the high ethanol content is needed to make the PEO-PPO polymer processable.
US 2003/0079644 discloses ink additives comprising 2-4 4H-units that are prepared from e.g. PEO-PPO polymers commercially available under the trade name VORANOL® from Dow Chemical Co., Midland, Mich., US, and 2(6-isocyanato-hexylaminocarbonylamino)-6-methyl-4(1H)-pyrimidone. According to the Examples XIII-XVI of US 2003/0079644, the ink compositions may comprise up to 5 wt. % of the polymer and water in the range of about 18 to about 35 wt. % and these compositions would have a viscosity at about 25° C. of no more than about 10 cP (cf. paragraphs [0174] and [0179] of US 2003/0079644). This implies that these polymers are not water gellants.
Because of the shortcomings of state-of-the-art hydrogels, there is a need for synthetic polymers that are able to gel water reversibly, implying that the hydrogels can be switched between a gelled state and a liquid state. This would facilitate easy processing and administration of these hydrogels. In addition, it is desired that hydrogels can be tuned with respect to their mechanical properties to be able to meet the requirements of specific applications. Also, it would be advantageous to be able to make biodegradable reversible hydrogels.